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WO2001096262A1 - Procede de realisation de structures dendritiques - Google Patents

Procede de realisation de structures dendritiques Download PDF

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Publication number
WO2001096262A1
WO2001096262A1 PCT/DE2001/002230 DE0102230W WO0196262A1 WO 2001096262 A1 WO2001096262 A1 WO 2001096262A1 DE 0102230 W DE0102230 W DE 0102230W WO 0196262 A1 WO0196262 A1 WO 0196262A1
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WO
WIPO (PCT)
Prior art keywords
groups
reaction
bisubstituted
alkynyl halide
butyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/DE2001/002230
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German (de)
English (en)
Inventor
Manfred Wiessler
Stefan Raddatz
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Deutsches Krebsforschungszentrum DKFZ
Original Assignee
Deutsches Krebsforschungszentrum DKFZ
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Filing date
Publication date
Application filed by Deutsches Krebsforschungszentrum DKFZ filed Critical Deutsches Krebsforschungszentrum DKFZ
Publication of WO2001096262A1 publication Critical patent/WO2001096262A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G83/00—Macromolecular compounds not provided for in groups C08G2/00 - C08G81/00
    • C08G83/002—Dendritic macromolecules
    • C08G83/003—Dendrimers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical

Definitions

  • the invention relates to a method for producing dendritic structures.
  • Dendritic structures especially dendritic saccharide structures, have become increasingly important for biological applications in recent years. It has been recognized that dentritic structures play a role in biological recognition processes, e.g. in the case of metastasis or infection by viruses or bacteria (Varki, Glycobiology 1993, 3, 97). However, the reactions used to build up these structures all suffer from the disadvantage that they offer no possibility of introducing a wide variety of (sugar) structures in a few reaction steps.
  • the present invention is therefore based on the object of providing a method with which dendritic structures (in particular dendritic saccharide structures with high variability) can be produced simply, inexpensively, with high variability and in good yields.
  • the present application thus relates to a process in which highly substituted alkynyl halides are reacted with CH-acidic carbonyl compounds in the presence of a strong base.
  • Dendrimers / dendritic structures are three-dimensional, highly ordered oligomeric or polymeric compounds. These have several reactive groups. Substances are bound to these groups. In this way, first generation dendrimers are obtained. To the substances of the First generation dendrimers can be bound to other substances which can then be linked to other substances. Second generation dendrimers are obtained. By repeating this sequence of reactions, higher generation dendrimers are obtained.
  • the present invention is based on the finding that even highly substituted alkynyl halides can alkylate reactive CH-acidic compounds repeatedly (e.g. up to four times) in good to very good yields. Any ester groups or protective groups which may be present can then be split off and the remaining keto function reduced, so that an alcohol function is formed. This alcohol function can be alkylated again with a reactive alkynyl halide, which means the generation of a spacer in the resulting dendrimeric structure. Therefore, preferred spacers are saturated or unsaturated hydrocarbon chains, preferably C 2 -C 18 groups, which may contain heteroatoms, such as oxygen, sulfur or nitrogen atoms.
  • FIG. 1 A preferred reaction scheme for the production of dendrimeric saccharide structures is shown in FIG. 2.
  • any of a C-H-acidic carbonyl compound is any of a C-H-acidic carbonyl compound
  • Preferred C-H-acidic compounds are diethyl acetone dicarboxylate, acetoacetic ester, diethyl malonate, di (2-trimethylsilylethyl) acetone dicarboxylate, di-t-butyl acetone dicarboxylate.
  • an alkynyl halide is understood to mean all aliphatic, alicyclic or aromatic hydrocarbons which have an at least bisubstituted CC triple bond and have a halogen substituent.
  • the halogen substituent can be fluoride, bromide, chloride or iodide, with bromide being preferred.
  • Very preferred compounds are 2-alkynyl halides, such as 1-bromo-2-butyn-4-ol or 1-bromo-2-hexin-6-ol.
  • the alkynyl halides preferably have one on at least one of their ends -14/6
  • saccharide encompasses saccharides of all kinds, in particular monosaccharides in all stereoisomeric and enantiomeric forms, for example pentoses and hexoses, such as ⁇ - and ⁇ -D-glucose and derivatives thereof, such as with protecting groups, for example benzyl-protected saccharides and / or with functional groups Groups such as amino groups, phosphate groups or halide groups, modified saccharides.
  • Saccharides here are especially inositols, very particularly optically active derivatives of myo-inositol and quebrachitol, for example from galactinols, both from plant sources, such as sugar beets, and from milk products, or derivatives obtained by enzymatic separation of enantiomers.
  • the saccharides can be the same or different from one another. Between the actual alkyl halide and the
  • a spacer as defined above is present between the core structure originating from the C-H-acidic compound and one or at most all of the end modifications (e.g. saccharides). If there are several spacers, they can be the same or different from one another.
  • phase the necessary base (e.g. hydroxide) is dissolved in water.
  • the conditions in which the components react with one another can be determined by a person skilled in the art.
  • the ratio of the components is preferably:
  • the reaction times can be between 2 and 24, preferably between 5 and 20, very preferably 8 to 15 hours.
  • the reaction temperatures are between 0 ° C and 60 ° C, preferably between 20 and 40 ° C, very preferably at room temperature to about 30 ° C.
  • Fig. 3 shown.
  • Dendrimers produced according to the invention are notable for a number of advantageous properties. They are biodegradable. Therefore, they are easy to dispose of. Furthermore, they are essentially renewable
  • dendrimers according to the invention are present in precisely defined structures, ie there are no defects and / or inter- or intramolecular bonds. Furthermore, dendrimers according to the invention have chiral C atoms. In addition, due to their structure, they can be chemical
  • dendrimers according to the invention are able to enter into elective interactions with sugar-specific receptors and thus e.g. bind to viruses, bacteria and cells.
  • dendrimers produced according to the invention are ideally suited as column material for separating substances from mixtures of products, in particular for separating racemates into enantiomers. Furthermore, they can due to their interactions with receptors for the affinity chromatographic isolation of lectins and other glycoproteins and as cell adhesion inhibitors, for example viruses and bacteria for infection protection.
  • dendrimers produced according to the invention can be provided for a large number of other uses.
  • they can be used as catalysts in enatioselective synthesis. They are also suitable in the medical field, e.g. as a carrier of medicinal substances, in particular for use in depot medication and for the targeted injection of active substances into target cells (drug targeting). Furthermore, they can be used to prevent rejection reactions in organ transplants.
  • Dendrimers according to the invention can also be used for the surface coating of aqueous media and as micelles. Furthermore, they can, especially if they carry functional groups such as amino groups in the outermost shell
  • dendrimers according to the invention which are conjugated to solid phases, in particular derivatives of inositol, can be used for the treatment of drinking water contaminated with bacteria.
  • dendrimers according to the invention if they are linked to dyes, can be used to label lectins in histochemical and cytochemical processes.
  • Fig. 2 Structure of a dendrimeric structure starting from a galactose-modified alkynyl bromide and acetone dicarboxylic acid ester
  • Fig. 3 Structure of a dendrimeric structure based on a sugar-modified alkynyl bromide and acetoacetic ester -10/6
  • Example 1 Preparation of 1 -Brom ⁇ a'jS ' ⁇ 'je'-tetra-O-benzyl- ⁇ -D-glucopyranosyl] -but-2-in (43) and benzy! -ß-D-glucopyranosyl] -but-2-in (43ß)
  • reaction mixture was shaken with saturated sodium bicarbonate solution and the organic phase was separated off.
  • the aqueous phase was extracted twice more with dichloromethane.
  • the organic phases were combined and dried over anhydrous sodium sulfate. It was concentrated and the residue was removed using
  • Example 2 Preparation of l-Bro - -t 'jS' ⁇ '- ⁇ '-tetra ⁇ OJ-benzyl- ⁇ -D-galactopyranosyl] -but-2-in (44) 3.51 g (5.12 mmol) [2, 3, 4, 6-tetra- (O) -benzy! -Ss-D-galactogyranosyl] - trichloroacetim.dat [Schmidt 1980] and 879 mg (10.2 mmol) of 2-butyne-1, 4-diol were in 15 ml abs , Acetonitrile suspended. The mixture was cooled to 15 ° C. and 150 l ( ⁇ 184 mg, 0.82 mmol) of trimethylsilyl trifluoromethanesulfonate were added dropwise. After thirty minutes
  • Example 4 Preparation of 2,2-bis [4'- ⁇ -D-glucopyranosyI-butyl] - di-tert-butyl malonic acid (48) 20.2 mg (14.5 // mol) 2,2-bis [4 '- (2nd ", 3", 4 ", 6" -Tetra- (O) -benzyl- ⁇ -D-glucosyl) -but-2'-inyl] malonic acid di-tert-butyl ester 47 and 6.9 mg of 20% Pd / C were suspended in 1.0 ml acetone / water (9: 1) under a hydrogen atmosphere. The mixture was stirred at RT for 16 hours.
  • reaction mixture was filtered through a membrane filter and the filtrate was concentrated on a rotary evaporator.
  • the residue could be purified by filtration through silica gel using methanol as the eluent. A colorless oil was isolated.
  • Example 6 Preparation of 2 5 2,4,4-tetrakis [4 '- (»- D-glucopyranosyl) butyl] -3-oxoglutaric acid di-tert-butyl ester (50) 17.2 mg (6.56 mol) 2,2,4 , 4-TetrakisI4 '- (2 ", 3", 4 ", 6" -Tetra- (0 -benzyl- -D-glucopyranosyl) -but-2'-ynyl] -3-oxoglutaric acid di-tert-butyl ester (49 ) and 5.8 mg of 20% Pd / C were suspended under a hydrogen atmosphere in 1.0 ml of acetone / water (9: 1) and reacted and worked up as described in regulation 48. The residue was purified by column chromatography, and a colorless oil was isolated. 14

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biochemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Molecular Biology (AREA)
  • Biotechnology (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Polymers & Plastics (AREA)
  • Saccharide Compounds (AREA)

Abstract

L'invention concerne un procédé selon lequel des halogénures d'alkinyle plusieurs fois substitués sont mis à réagir avec des composés carbonyle acides CH en présence d'un agent de réduction.
PCT/DE2001/002230 2000-06-16 2001-06-13 Procede de realisation de structures dendritiques Ceased WO2001096262A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10029709A DE10029709A1 (de) 2000-06-16 2000-06-16 Verfahren zur Herstellung von dendritischen Strukturen
DE10029709.9 2000-06-16

Publications (1)

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WO2001096262A1 true WO2001096262A1 (fr) 2001-12-20

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9383364B2 (en) 2011-03-07 2016-07-05 University Of Louisville Research Foundation, Inc. Predictive marker of DNMT1 inhibitor therapeutic efficacy and methods of using the marker
US9737493B2 (en) 2012-09-07 2017-08-22 University Of Louisville Research Foundation, Inc. Compositions and methods for modulating DNMT1 inhibitor activity

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2111385B1 (fr) 2007-02-06 2014-11-12 University Of Louisville Research Foundation, Inc. Alcynes substitués comme agents antitumoraux

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19624705A1 (de) * 1996-06-20 1998-01-08 Deutsches Krebsforsch Dendrimere auf Saccharid-Basis

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19624705A1 (de) * 1996-06-20 1998-01-08 Deutsches Krebsforsch Dendrimere auf Saccharid-Basis

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
B. KÖNIG ET AL.: "Synthesis of macrocyclic enediynes by twofold C-alkylation", SYNTHESIS, 1996, pages 446 - 448, XP002177791 *
R.S. ATKINSON, M.J. GRIMSHIRE: "Intramolecular reactions of N-nitrenes with alkynes: Conformational anchoring in spiro-fused 2H-azirines", J. CHEM. SOC. PERKIN TRANS. I, 1986, pages 1215 - 1224, XP002177790 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9383364B2 (en) 2011-03-07 2016-07-05 University Of Louisville Research Foundation, Inc. Predictive marker of DNMT1 inhibitor therapeutic efficacy and methods of using the marker
US9737493B2 (en) 2012-09-07 2017-08-22 University Of Louisville Research Foundation, Inc. Compositions and methods for modulating DNMT1 inhibitor activity

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Publication number Publication date
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